Hormones and Cerebellar Development

  • Noriyuki Koibuchi
  • Yayoi Ikeda


Cerebellar development involves various epigenetic processes that activate specific genes at different time points. The epigenetic influences include humoral influences from endocrine cells. Among circulating hormones, a group of small lipophilic hormones such as steroids (corticosteroids, progesterone, androgens, and estrogens) and thyroid hormone may particularly serve an important role in mediating environmental influences to the cerebellum. Receptors for such lipophilic hormones are mainly located in the cell nucleus (nuclear receptor, NR), and represent the largest family of ligand-regulated transcription factors. In the cerebellum, these are expressed in a specific temporal and spatial pattern. Among lipophilic hormones, involvement of thyroid hormone and gonadal steroids on cerebellar development has been well studied. Deficiency of thyroid hormone during postnatal development results in abnormal cerebellar morphogenesis in rodents. Estrogen and progesterone also play an important role in this process. In addition to the supply from circulation, several gonadal steroids are produced locally within the Purkinje cell (neurosteroids). In this chapter, the effect of thyroid and steroid hormones are separately discussed. Neurosteroids that are locally synthesized in the cerebellum are discussed in  Chap. 42, “Neurosteroids and Synaptic Formation in the Cerebellum”.


Thyroid Hormone Purkinje Cell Cerebellar Granule Cell Thyroid Hormone Receptor Gonadal Steroid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abel ED, Boers ME, Pazos-Moura C et al (1999) Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system. J Clin Invest 104:291–300PubMedCrossRefGoogle Scholar
  2. Aden P, Goverud I, Liestøl K et al (2008) Low-potency glucocorticoid hydrocortisone has similar neurotoxic effects as high-potency glucocorticoid dexamethasone on neurons in the immature chicken cerebellum. Brain Res 1236:39–48PubMedCrossRefGoogle Scholar
  3. Ahlbom E, Gogvadze V, Chen M et al (2000) Prenatal exposure to high levels of glucocorticoids increases the susceptibility of cerebellar granule cells to oxidative stress-induced cell death. Proc Natl Acad Sci USA 97:14726–14730PubMedCrossRefGoogle Scholar
  4. Ahlbom E, Prins GS, Ceccatelli S (2001) Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism. Brain Res 892:255–262PubMedCrossRefGoogle Scholar
  5. Bakker J, Brock O (2010) Early oestrogens in shaping reproductive networks: evidence for a potential organisational role of oestradiol in female brain development. J Neuroendocrinol 22:728–735PubMedGoogle Scholar
  6. Balázs R, Brooksbandk BWL et al (1971) Incorporation of [35 S] sulfate into brain constituents during development and the effects of thyroid hormone on myelination. Brain Res 30:273–293PubMedCrossRefGoogle Scholar
  7. Baldaçara L, Borgio JG, Lacerda AL et al (2008) Cerebellum and psychiatric disorders. Rev Bras Psiquiatr 30:281–289PubMedCrossRefGoogle Scholar
  8. Bates JM, St Germain DL, Galton VA (1999) Expression profiles of the three iodothyronine deiodinases, D1, D2, and D3, in the developing rat. Endocrinology 140:844–851PubMedCrossRefGoogle Scholar
  9. Belcher SM (2008) Rapid signaling mechanisms of estrogens in the developing cerebellum. Brain Res Rev 57:481–492PubMedCrossRefGoogle Scholar
  10. Belcher SM, Le HH, Spurling L et al (2005) Rapid estrogenic regulation of extracellular signal-regulated kinase 1/2 signaling in cerebellar granule cells involves a G protein- and protein kinase A-dependent mechanism and intracellular activation of protein phosphatase 2A. Endocrinology 146:5397–5406PubMedCrossRefGoogle Scholar
  11. Bernal J (2005) The significance of thyroid hormone transporter in the brain. Endocrinology 46:1698–1700CrossRefGoogle Scholar
  12. Biamonte F, Assenza G, Marino R et al (2009) Interactions between neuroactive steroids and reelin haploinsufficiency in Purkinje cell survival. Neurobiol Dis 36:103–115PubMedCrossRefGoogle Scholar
  13. Bohn MC, Lauder JM (1980) Cerebellar granule cell genesis in the hydrocortisone-treated rats. Dev Neurosci 3:81–89PubMedCrossRefGoogle Scholar
  14. Bookout AL, Jeong Y, Downes M et al (2006) Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126:789–799PubMedCrossRefGoogle Scholar
  15. Bradley DJ, Towle HC, Young WS (1992) Spatial and temporal expression of α- and β-thyroid hormone receptor mRNAs, including the β2-subtype, in the developing mammalian nervous system. J Neurosci 12:2288–2302PubMedGoogle Scholar
  16. Calvo R, Obregón MJ, Ruiz de Oña C et al (1990) Congenital hypothyroidism, as studied in rats. J Clin Invest 86:889–899PubMedCrossRefGoogle Scholar
  17. Chassande O (2003) Do unliganded thyroid hormone receptors have physiological functions? J Mol Endocrinol 31:9–20PubMedCrossRefGoogle Scholar
  18. Daré E, Götz ME, Zhivotovsky B et al (2000) Antioxidants J811 and 17beta-estradiol protect cerebellar granule cells from methylmercury-induced apoptotic cell death. J Neurosci Res 62:557–565PubMedCrossRefGoogle Scholar
  19. Darras VM (2008) Endocrine disrupting polyhalogenated organic pollutants interfere with thyroid hormone signaling in the developing brain. Cerebellum 7:26–37PubMedCrossRefGoogle Scholar
  20. Dean SL, McCarthy MM (2008) Steroids, sex and the cerebellar cortex: Implications for human disease. Cerebellum 7:38–47PubMedCrossRefGoogle Scholar
  21. Evanson NK, Herman JP, Sakai RR et al (2010) Nongenomic actions of adrenal steroids in the central nervous system. J Neuroendocrinol 22:846–861PubMedGoogle Scholar
  22. Fan X, Xu H, Warner M et al (2010) ERbeta in CNS: new roles in development and function. Prog Brain Res 181:233–250PubMedCrossRefGoogle Scholar
  23. Fatemi SH (2001) Reelin mutations in mouse and man: from reeler mouse to schizophrenia, mood disorders, autism and lissencephaly. Mol Psychiatry 6:129–133PubMedCrossRefGoogle Scholar
  24. Forrest D, Erway LC, Ng L, Altschuler R et al (1996) Thyroid hormone receptor beta is essential for development of auditory function. Nat Genet 13:354–357PubMedCrossRefGoogle Scholar
  25. Fraichard A, Chassande O, Plateroti M et al (1997) The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production. EMBO J 16:4412–4420PubMedCrossRefGoogle Scholar
  26. Frye CA (2001) The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents. Brain Res Rev 37:201–222PubMedCrossRefGoogle Scholar
  27. Gauthier K, Chassande O, Plateroti M et al (1999) Different functions for the thyroid hormone receptors TRα and TRβ in the control of thyroid hormone production and post-natal development. EMBO J 18:623–631PubMedCrossRefGoogle Scholar
  28. Gauthier K, Plateroti M, Harvey CB et al (2001) Genetic analysis reveals different functions for the products of the thyroid hormone receptor alpha locus. Mol Cell Biol 21:4748–4760PubMedCrossRefGoogle Scholar
  29. Goldstein JM, Link BG (1988) Gender and the expression of schizophrenia. J Psychiatr Res 22:141–155PubMedCrossRefGoogle Scholar
  30. Göthe S, Wang Z, Ng L et al (1999) Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev 13:1329–1341PubMedCrossRefGoogle Scholar
  31. Gottfried-Blackmore A, Croft G, McEwen BS et al (2007) Transcriptional activity of estrogen receptors ERα and ERβ in the EtC.1 cerebellar granule cell line. Brain Res 1186:41–47PubMedCrossRefGoogle Scholar
  32. Guadaño-Ferraz A, Obregón MJ, St Germain DL et al (1997) The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain. Proc Natl Acad Sci USA 94:10391–10396PubMedCrossRefGoogle Scholar
  33. Guadaño-Ferraz A, Benavides-Piccione R, Venero C et al (2003) Lack of thyroid hormone receptor alpha1 is associated with selective alterations in behavior and hippocampal circuits. Mol Psychiatry 8:30–38PubMedCrossRefGoogle Scholar
  34. Hajós F, Patel AJ, Balázs R (1973) Effect of thyroid deficiency on the synaptic organization of the rat cerebellar cortex. Brain Res 50:387–401PubMedCrossRefGoogle Scholar
  35. Hashimoto K, Curty FH, Borges PP et al (2001) An unliganded thyroid hormone receptor causes severe neurological dysfunction. Proc Natl Acad Sci USA 98:3998–4003PubMedCrossRefGoogle Scholar
  36. Ibhazehiebo K, Iwasaki T, Kimura-Kuroda J et al (2011a) Disruption of thyroid hormone receptor-mediated transcription and thyroid hormone-induced Purkinje cell dendrite arborization by polybrominated diphenyl ethers. Environ Health Perspect 119:168–175PubMedCrossRefGoogle Scholar
  37. Ibhazehiebo K, Iwasaki T, Xu M, Shimokawa N et al (2011b) Brain-derived neurotrophic factor (BDNF) ameliorates the suppression of thyroid hormone-induced granule cell neurite extension by hexabromocyclododecane (HBCD). Neurosci Lett 493:1–7PubMedCrossRefGoogle Scholar
  38. Ikeda Y, Nagai A (2006) Differential expression of the estrogen receptors alpha and beta during postnatal development of the rat cerebellum. Brain Res 1083:39–49PubMedCrossRefGoogle Scholar
  39. Ikeda Y, Nagai A, Ikeda MA et al (2003) Sexually dimorphic and estrogen-dependent expression of estrogen receptor beta in the ventromedial hypothalamus during rat postnatal development. Endocrinology 144:5098–5104PubMedCrossRefGoogle Scholar
  40. Itoh Y, Esaki T, Kaneshige M et al (2001) Brain glucose utilization in mice with a targeted mutation in the thyroid hormone α or β receptor gene. Proc Natl Acad Sci USA 98:9913–9918PubMedCrossRefGoogle Scholar
  41. Jakab RL, Wong JK, Belcher SM (2001) Estrogen receptor-ß immunoreactivity in differentiating cells of the developing rat cerebellum. J Comp Neurol 430:396–409PubMedCrossRefGoogle Scholar
  42. Kelly MJ, Qiu J (2010) Estrogen signaling in hypothalamic circuits controlling reproduction. Brain Res 1364:44–52PubMedCrossRefGoogle Scholar
  43. Kester MH, Martinez de Mena R, Obregon MJ et al (2004) Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas. J Clin Endocrinol Metab 89:3117–3128PubMedCrossRefGoogle Scholar
  44. Knickmeyer RC, Baron-Cohen S (2006) Fetal testosterone and sex differences in typical social development and in autism. J Child Neurol 21:825–845PubMedCrossRefGoogle Scholar
  45. Koibuchi N (2009) Animal models to study thyroid hormone action in cerebellum. Cerebellum 8:89–97PubMedCrossRefGoogle Scholar
  46. Koibuchi N, Yamaoka S, Chin WW (2001) Effects of altered thyroid status in neurotrophin gene expression during postnatal development of the mouse cerebellum. Thyroid 11:205–210PubMedCrossRefGoogle Scholar
  47. Koibuchi N, Jingu H, Iwasaki T et al (2003) Current perspectives on the role of thyroid hormone in growth and development of cerebellum. Cerebellum 2:279–289PubMedCrossRefGoogle Scholar
  48. Koopman P, Gubbay J, Vivian N et al (1991) Male development of chromosomally female mice transgenic for Sry. Nature 351:117–121PubMedCrossRefGoogle Scholar
  49. Kudwa AE, Michopoulos V, Gatewood JD et al (2006) Roles of estrogen receptors alpha and beta in differentiation of mouse sexual behavior. Neuroscience 138:921–928PubMedCrossRefGoogle Scholar
  50. Lavaque E, Mayen A, Azcoitia I et al (2006) Sex differences, developmental changes, response to injury and cAMP regulation of the mRNA levels of steroidogenic acute regulatory protein, cytochrome p450scc, and aromatase in the olivocerebellar system. J Neurobiol 66:308–318PubMedCrossRefGoogle Scholar
  51. Lawson A, Ahima RS, Krozowski Z et al (1992) Postnatal development of corticosteroid receptor immunoreactivity in the rat cerebellum and brain stem. Neuroendocrinology 55:695–707PubMedCrossRefGoogle Scholar
  52. Lazar MA (1993) Thyroid hormone receptors: multiple forms, multiple possibilities. Endocrine Rev 14:184–193Google Scholar
  53. Llorente R, Gallardo ML, Berzal AL et al (2009) Early maternal deprivation in rats induces gender-dependent effects on developing hippocampal and cerebellar cells. Int J Dev Neurosci 27:233–241PubMedCrossRefGoogle Scholar
  54. Macchia PE, Takeuchi Y, Kawai T et al (2001) Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor alpha. Proc Natl Acad Sci USA 98:349–354PubMedGoogle Scholar
  55. Mangelsdorf DJ, Thummel C, Beato M et al (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839PubMedCrossRefGoogle Scholar
  56. Martin LA, Goldowitz D, Mittleman G (2010) Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism. Eur J Neurosci 31:544–555PubMedCrossRefGoogle Scholar
  57. Martinez de Arrieta C, Koibuchi N, Chin WW (2000) Coactivator and corepressor gene expression in rat cerebellum during postnatal development and the effect of altered thyroid status. Endocrinology 141:1693–1698PubMedCrossRefGoogle Scholar
  58. Messer A, Maskin P, Snodgrass GL (1984) Effects of triiodothyronine (T3) on the development of rat cerebellar cells in culture. Int J Dev Neurosci 2:277–285CrossRefGoogle Scholar
  59. Miñano A, Cerbón MA, Xifró X (2007) 17beta-estradiol does not protect cerebellar granule cells from excitotoxicity or apoptosis. J Neurochem 102:354–364PubMedCrossRefGoogle Scholar
  60. Morte B, Manzano J, Scanlan T et al (2002) Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism. Proc Natl Acad Sci USA 99:3985–3989PubMedCrossRefGoogle Scholar
  61. Morte B, Manzano J, Scanlan TS et al (2004) Aberrant maturation of astrocytes in thyroid hormone receptor alpha 1 knockout mice reveals an interplay between thyroid hormone receptor isoforms. Endocrinology 145:1386–1391PubMedCrossRefGoogle Scholar
  62. Ng L, Hurley JB, Dierks B et al (2001) A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nat Genet 27:94–98PubMedGoogle Scholar
  63. Nguon K, Ladd B, Baxter MG et al (2005) Sexual dimorphism in cerebellar structure, function, and response to environmental perturbations. Prog Brain Res 148:199–212CrossRefGoogle Scholar
  64. Nicholson JL, Altman J (1972a) The effects of early hypo- and hyperthyroidism on the development of the rat cerebellar cortex. II. Synaptogenesis in the molecular layer. Brain Res 44:25–36PubMedCrossRefGoogle Scholar
  65. Nicholson JL, Altman J (1972b) Synaptogenesis in the rat cerebellum: effects of early hypo- and hyperthyroidism. Science 176:530–532PubMedCrossRefGoogle Scholar
  66. Nicholson JL, Altman J (1972c) The effects of early hypo- and hyperthyroidism on development of rat cerebellar cortex. I. Cell proliferation and differentiation. Brain Res 44:13–23PubMedCrossRefGoogle Scholar
  67. Nishihara E (2008) An overview of nuclear receptor coregulators involved in cerebellar development. Cerebellum 7:48–59PubMedCrossRefGoogle Scholar
  68. Nishihara E, Yoshida-Komiya H, Chan CS et al (2003) SRC-1 null mice exhibit moderate motor dysfunction and delayed development of cerebellar Purkinje cells. J Neurosci 23:213–222PubMedGoogle Scholar
  69. Noguchi KK, Walls KC, Wozniak DF et al (2008) Acute neonatal glucocorticoid exposure produces selective and rapid cerebellar neural progenitor cell apoptotic death. Cell Death Differ 15:1582–1592PubMedCrossRefGoogle Scholar
  70. Poguet AL, Legrand C, Feng X et al (2003) Microarray analysis of knockout mice identifies cyclin D2 as a possible mediator for the action of thyroid hormone during the postnatal development of the cerebellum. Dev Biol 254:188–199PubMedCrossRefGoogle Scholar
  71. Prager EM, Johnson LR (2009) Stress at the synapse: signal transduction mechanisms of adrenal steroids at neuronal membranes. Sci Signal 2:re5PubMedCrossRefGoogle Scholar
  72. Qin J, Suh JM, Kim BJ et al (2007) The expression pattern of nuclear receptors during cerebellar development. Dev Dyn 236:810–820PubMedCrossRefGoogle Scholar
  73. Qiu C-H, Shimokawa N, Iwasaki T et al (2007) Alteration of cerebellar neurotrophin messenger ribonucleic acids and the lack of thyroid hormone receptor augmentation by staggerer- type retinoic acid receptor-related orphan receptor-α mutation. Endocrinology 148:1745–1753PubMedCrossRefGoogle Scholar
  74. Qiu C-H, Miyazaki W, Iwasaki T et al (2009) Retinoic Acid receptor-related orphan receptor alpha-enhanced thyroid hormone receptor-mediated transcription requires its ligand binding domain which is not, by itself, sufficient: possible direct interaction of two receptors. Thyroid 19:893–898PubMedCrossRefGoogle Scholar
  75. Rashid S, Lewis GF (2005) The mechanisms of differential glucocorticoid and mineralocorticoid action in the brain and peripheral tissues. Clin Biochem 38:401–409PubMedCrossRefGoogle Scholar
  76. Raz L, Khan MM, Mahesh VB et al (2008) Rapid estrogen signaling in the brain. Neurosignals 16:140–153PubMedCrossRefGoogle Scholar
  77. Refetoff S, Weiss RE, Usala SJ (1993) The syndromes of resistance to thyroid hormone. Endocr Rev 14:348–399PubMedGoogle Scholar
  78. Rosenfeld MG, Lunyak VV, Glass CK (2006) Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 20:1405–1428PubMedCrossRefGoogle Scholar
  79. Rugerio-Vargas C, Ramírez-Escoto M, DelaRosa-Rugerio C et al (2007) Prenatal corticosterone influences the trajectory of neuronal development, delaying or accelerating aspects of the Purkinje cell differentiation. Histol Histopathol 22:963–969PubMedGoogle Scholar
  80. Sakamoto H, Mezaki Y, Shikimi H et al (2003) Dendritic growth and spine formation in response to estrogen in the developing Purkinje cell. Endocrinology 144:4466–4477PubMedCrossRefGoogle Scholar
  81. Sakamoto H, Ukena K, Kawata M et al (2008) Expression, localization and possible actions of 25-Dx, a membrane-associated putative progesterone-binding protein, in the developing Purkinje cell of the cerebellum: a new insight into the biosynthesis, metabolism and multiple actions of progesterone as a neurosteroid. Cerebellum 7:18–25PubMedCrossRefGoogle Scholar
  82. Saltó C, Kindblom JM, Johansson C et al (2001) Ablation of TRα2 and a concomitant overexpression of alpha1 yields a mixed hypo- and hyperthyroid phenotype in mice. Mol Endocrinol 15:2115–2128PubMedCrossRefGoogle Scholar
  83. Sandhofer C, Schwartz HL, Mariash CN et al (1998) Beta receptor isoforms are not essential for thyroid hormone-dependent acceleration of PCP-2 and myelin basic protein gene expression in the developing brains of neonatal mice. Mol Cell Endocrinol 137:109–115PubMedCrossRefGoogle Scholar
  84. Suzuki T, Abe T (2008) Thyroid hormone transporters in the brain. Cerebellum 7:75–83PubMedCrossRefGoogle Scholar
  85. Thompson CC, Bottcher M (1997) The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors. Proc Natl Acad Sci USA 94:8527–8532PubMedCrossRefGoogle Scholar
  86. Tsutsui K (2006) Biosynthesis and organizing action of neurosteroids in the developing Purkinje cell. Cerebellum 5:89–96PubMedCrossRefGoogle Scholar
  87. Tu HM, Legradi G, Bartha T et al (1999) Regional expression of the type 3 iodothyronine deiodinase messenger ribonucleic acid in the rat central nervous system and its regulation by thyroid hormone. Endocrinology 140:784–790PubMedCrossRefGoogle Scholar
  88. Vasudevan N, Pfaff DW (2008) Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol 29:238–257PubMedCrossRefGoogle Scholar
  89. Velazquez PN, Romano MC (1987) Corticosterone therapy during gestation: effects on the development of rat cerebellum. Int J Dev Neurosci 5:189–194PubMedCrossRefGoogle Scholar
  90. Viveros MP, Llorente R, López-Gallardo M et al (2009) Sex-dependent alterations in response to maternal deprivation in rats. Psychoneuroendocrinology 34(Suppl 1):S217–226PubMedCrossRefGoogle Scholar
  91. Walker CD, Kanand JS, Plotsky PM (2001) Development of the hypothalamic–pituitary–adrenal axis and the stress response. In: McEwen BS (ed) Handbook of physiology: coping with the environment. Oxford University Press, New YorkGoogle Scholar
  92. Wilber AA, Wellman CL (2009) Neonatal maternal separation alters the development of glucocorticoid receptor expression in the interpositus nucleus of the cerebellum. Int J Dev Neurosci 27:649–654PubMedCrossRefGoogle Scholar
  93. Wilson ME, Westberry JM (2009) Regulation of oestrogen receptor gene expression: new insights and novel mechanisms. J Neuroendocrinol 21:238–242PubMedCrossRefGoogle Scholar
  94. Wright CL, Schwarz JS, Dean SL et al (2010) Cellular mechanisms of estradiol-mediated sexual differentiation of the brain. Trends Endocrinol Metab 21:553–561PubMedCrossRefGoogle Scholar
  95. Wu Y, Koenig RJ (2000) Gene regulation by thyroid hormone. Trends Endocrinol Metab 11:207–211PubMedCrossRefGoogle Scholar
  96. Yamate S, Nishigori H, Kishimoto S et al (2010) Effects of glucocorticoid on brain acetylcholinesterase of developing chick embryos. J Obstet Gynaecol Res 36:11–18PubMedCrossRefGoogle Scholar
  97. Yousefi B, Jingu H, Ohta M et al (2005) Postnatal changes of steroid receptor coactivator-1 immunoreactivity in rat cerebellar cortex. Thyroid 15:314–319PubMedCrossRefGoogle Scholar
  98. Zhang JM, Konkle AT, Zup SL et al (2008) Impact of sex and hormones on new cells in the developing rat hippocampus: a novel source of sex dimorphism? Eur J Neurosci 27:791–800PubMedCrossRefGoogle Scholar
  99. Zuloaga DG, Puts DA, Jordan CL et al (2008) The role of androgen receptors in the masculinization of brain and behavior: what we've learned from the testicular feminization mutation. Horm Behav 53:613–626PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Integrative PhysiologyGunma University Graduate School of MedicineMaebashiJapan
  2. 2.Department of Histology and Cell BiologyYokohama City University School of MedicineYokohamaJapan

Personalised recommendations